A-hydroxynitriles

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The reduction of a-hydroxynitriles to yield vicinal amino alcohols is conveniently accomplished with complex metal hydrides for example, lithium aluminum hydride or sodium borohydride [69]. However, it is still worth noting that a two-step chemo-enzymatic synthesis of (R)-2-amino-l-(2-furyl)ethanol for laboratory production was developed followed by successful up-scaling to kilogram scale using NaBH4/CF3COOH as reductant [70],... 

The activities of NHases from Rhodococcus sp. Adpl2 and Gordonia sp. BR-1 strains have been partially characterized [25]. In reactions that catalyze the hydration of a-hydroxynitriles such as lactonitrile or glycolonitrile, the substrate can dissociate to produce HCN and the corresponding aldehydes. HCN can inhibit and/or inactivate NHase, and it was determined that these two enzymes remain active in the presence of cyanide ion at concentrations up to 20 him. The dependence of the NHase activity of cell-free extracts of Rhodococcus rhodochrous J1 and Gordonia sp. BR-1 on cyanide ion concentration is illustrated in Figure 8.1, demonstrating the improved cyanide stability of BR-1 NHase relative to that of Jl. 

The different steric hindrance of hydroxyl groups in (3R)- and (3S)-cyanohydrins was revealed by activation of a-hydroxynitriles through O-tosylation to afford the (R)-tosylate in 85% yield and the (S)-tosylate in... 

Crystallisation studies using the PaHnl have also been reported [50]. Four isomeric forms of this Hnl were isolated from the aforementioned defatted almond meal and subsequently separated. Three of these isoenzymes were successfully crystallised and shown to belong to the monoclinic space group. Though by this means additional data were included, the clearest picture for the 3D structure of a hydroxynitrile lyase still remains with the HbHnl. 

Oxynitrilases are enzymes that catalyze the formation and cleavage of cyanohydrins through the stereoselective addition of hydrogen cyanide to aldehydes or methyl ketones giving enantiopure a-hydroxynitriles. The use of (R)-oxynitrilases for the preparation of chiral cyanohydrins has dramatically grown in the last decade because of their possibihties as precursors for the synthesis of many compounds with physiological properties [50]. 

The nitrile group in the readily available a-hydroxynitriles (the cyanohydrins) may also be similarly hydrolytically converted into a carboxyl group to afford a convenient synthesis of a-hydroxy acids (Expt 5.168). 

In the introduction to Chapter 9, it was mentioned that cyanide ions behave towards carbonyl compounds like the majority of O-, S- and Nnucleophiles. They add to the C=0 double bond. By taking up a proton the carbonyl oxygen is transformed into the OH group of a so-called cyanohydrin, i.e., a hydroxynitrile with geminal OH- and C=N groups. The classical transformation of this type is is effected by treatment of a carbonyl compound with both sodium... 

Although nitriles lack an acyl group, they are considered acid derivatives because they hydrolyze to carboxylic acids. Nitriles are frequently made from carboxylic acids (with the same number of carbons) by conversion to primary amides followed by dehydration. They are also made from primary alkyl halides and tosylates (adding one carbon) by nucleophilic substitution with cyanide ion. Aryl cyanides can be made by the Sandmeyer reaction of an aryldiazonium salt with cuprous cyanide. a-Hydroxynitriles (cyanohydrins) are made by the reaction of ketones and aldehydes with HCN. 

In this chapter deracemization methods for the preparation of multifunctional compounds (a- and P-hydroxy acids, a-hydroxynitriles, and a-amino acids) are discussed (Scheme 13.1). 

In the first step, cyanogenic glucosides are cleaved by p-glucosidases. The resulting a-hydroxynitriles are unstable and dissociate to produce a carbonyl compound and HCN. In many plants, the dissociation of the cyanohydrins is accelerated by an HNL. In plants that accumulate diglucosidic compounds, the hydrolysis of these substances can be achieved by either a sequential or a simultaneous mechanism (Kuroki et al, 1984) (Fig. 3.5). 

Hughes, J., de Carvalho, F.J.P and Hughes, M.A. (1994) Purification, characterization and cloning of a-hydroxynitrile lyase from cassava (Manihot esculenta Crantz). Ardz. 

Selmar, D., Lieberei, R., Biehl, B. and Conn, E.E. (1989) a-Hydroxynitrile lyase in Hevea brasiliensis and its significance for rapid cyanogenesis. Physiol. Plantarum, 75, 97-101. 

Cyanohydrin Compound of the general type R2C(OH)CN also called a hydroxynitrile. 

Oxynitrilases or hydroxynitrile lyases (HNL) constitute a group of enzymes that catalyze the reversible addition of HCN to ketones and aldehydes. The natural role of these enzymes is a defence mechanism of higher plants against herbivores, whereby HCN is liberated from cyanoglucosides such as prunasin (almond, cherry, apple) by the action of a glycosidase and a hydroxynitrile lyase. 

Enantiomerically pure cyanohydrins can easily be modified chemically or enzymatically (Scheme 4.12B), providing access to chiral a-hydroxy acids, a-hydroxy amides, 2-aminoalcohols, and epoxides. Replacement of the hydroxyl functionahty by a better leaving group, such as a sulfonyl moiety (e.g. tosylate), allows the introduction of various other nucleophiles with inversion at the stereocenter [51a]. The structures of some bioactive molecules that have been synthesized using a biotransformation step with a hydroxynitrile lyase are depicted in Scheme 4.12B [51a, 52]. 

These two methods involve the potential release of toxic HCN during the reaction and a cleaner as well as a safer method is to use acetone cyanohydrin 128 as a cyanide transfer reagent. The enzyme from the Brazilian rubber tree Hevea brasiliensis, called a hydroxynitrile lyase, catalyses cyanohydrin formation from aliphatic as well as aromatic aldehydes.40... 

In the last decade, optically pure cyanohydrins (a-hydroxynitriles) have become a versatile source for the synthesis of a variety of chiral building blocks. Diverse methods for the enantioselective synthesis of cyanohydrins have been published and reviewed111. Besides enzyme catalyzed methods, hydrocyanation or silylcyanation of aldehydes or ketones controlled by chiral metal complexes or cyclic dipeptides, as well as diastereoselective hydrocyanation of chiral carbonyl compounds, have been applied with moderate success. 

---